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US20030114442A1 - Substituted piperazine derivatives as mtp inhibitors - Google Patents

Substituted piperazine derivatives as mtp inhibitors Download PDF

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US20030114442A1
US20030114442A1 US10/168,926 US16892602A US2003114442A1 US 20030114442 A1 US20030114442 A1 US 20030114442A1 US 16892602 A US16892602 A US 16892602A US 2003114442 A1 US2003114442 A1 US 2003114442A1
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alkyl
phenyl
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fluorene
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Armin Heckel
Thorsten Lehmann-Lintz
Leo Thomas
Michael Mark
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Boehringer Ingelheim Pharma GmbH and Co KG
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Assigned to BOEHRINGER INGELHEIM PHARMA KG reassignment BOEHRINGER INGELHEIM PHARMA KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MARK, MICHAEL, THOMAS, LEO, LEHMANN-LINTZ, THORSTEN, HECKEL, ARMIN
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to substituted piperazine derivatives of general formula
  • the compounds of the above general formula I are valuable inhibitors of the microsomal triglyceride-transfer protein (MTP) and are therefore suitable for lowering the plasma level of the atherogenic lipoproteins.
  • MTP microsomal triglyceride-transfer protein
  • n denotes the number 2, 3, 4 or 5
  • X denotes a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or N-(C 1-3 -alkyl)-imino group
  • Y a denotes a carbonyl or sulphonyl group
  • Y b denotes the group —(CH 2 ) m —, wherein m denotes the number 2 or 3 and wherein a hydrogen atom may be replaced by a C 1-3 -alkyl group or a methylene group linked to a nitrogen atom may be replaced by a carbonyl group,
  • R a denotes a C 1-6 -alkoxy-, phenyl-C 1-3 -alkoxy or amino group, wherein the amino group may be mono- or disubstituted by C 1-3 -alkyl-, phenyl-C 1-4 -alkyl or phenyl groups and the substituents may be identical or different,
  • a phenyl-, naphthyl, tetrahydronaphthyl, phenoxy or heteroaryl group a C 1-9 -alkyl group optionally substituted by a hydroxy, C 1-3 -alkoxy, C 1-4 -alkoxycarbonyl or C 1-4 -alkyl-carbonyloxy group, which may be substituted in the alkyl moiety by a C 1-3 -alkyl group, by one or two phenyl groups, by a naphthyl, fluorenyl, phenoxy, heteroaryl or C 3-7 -cycloalkyl group, or a C 3-7 -cycloalkyl group substituted by a phenyl group,
  • R 1 denotes a hydrogen, fluorine, chlorine or bromine atom, a cyano, C 1-3 -alkyl, C 2-4 -alkenyl, phenyl, hydroxy, C 1-4 -alkoxy, phenyl-C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, N,N-di-(C 1-3 -alkyl)-aminocarbonyl, nitro, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, phenyl-C 1-3 -alkylamino, N-(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino, C 1-3 -alkylcarbonylamino, N-(C 1-3 -alkyl) —C 1-3 -alkylcarbonylamino,
  • R 2 denotes a hydrogen, fluorine, chlorine or bromine atom, a C 1-3 -alkyl, hydroxy or C 1-4 -alkoxy group, wherein in the abovementioned alkyl and alkoxy moieties of the groups R 1 and R 2 the hydrogen atoms may be wholly or partially replaced by fluorine atoms, or
  • R 1 and R 2 together denote a methylenedioxy group
  • R b denotes a carboxy, C 1-6 -alkoxycarbonyl, C 1-6 -alkoxycarbonyl-C 1-3 -alkylcarbonyl, C 3-7 -cycloalkoxycarbonyl or phenyl-C 1-3 -alkoxycarbonyl group or a R 3 NR 4 —CO group wherein
  • R 3 and R4 which may be identical or different, denote hydrogen atoms, C 1-6 -alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and the C 1-3 -alkyl moiety of a C 1-3 -alkylamino group may be substituted by a carboxy or C 1-3 -alkoxycarbonyl group or in the 2 or 3 position may also be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group, C 3-7 -cycloalkyl, pyridyl, pyridinyl-C 1-3 -alkyl, phenyl, naphthyl or phenyl-C 1-3 -alkyl groups, wherein the abovementioned phenyl groups may be substituted in each case by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl group wherein the
  • R 3 and R 4 together with the nitrogen atom between them denote a 3- to 7-membered cycloalkyleneimino group, wherein the methylene group in the 4 position of a 6 or 7-membered cycloalkyleneimino group may additionally be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N—(C 1-3 -alkyl)-imino group,
  • R c denotes a hydrogen atom or a C 1-3 -alkyl group
  • tricyclic group in the abovementioned general formula I may additionally be mono- or disubstituted by fluorine or chlorine atoms, by methyl or methoxy groups and the substituents may be identical or different,
  • heteroaryl groups by the abovementioned heteroaryl groups is meant a 6-membered heteroaryl group, containing one, two or three nitrogen atoms, or
  • a 5-membered heteroaryl group containing an imino group optionally substituted by a C 1-3 -alkyl group, an oxygen or sulphur atom or
  • an imino group optionally substituted by a C 1-3 -alkyl group and one or two nitrogen atoms or
  • a phenyl ring may be fused to the above-mentioned heteroaryl groups via a vinylene group
  • carboxy group mentioned in the definition of the abovementioned groups may be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions.
  • a group which may be converted in vivo into a carboxy group is meant, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol wherein the alcoholic moiety is preferably a C 1-6 -alkanol, a phenyl-C 1-3 -alkanol, a C 3-9 -cycloalkanol, wherein a C 5-8 -cycloalkanol may additionally be substituted by one or two C 1-3 -alkyl groups, a C 5-8 -cycloalkanol wherein a methylene group in the 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a C 1-3 -alkyl, phenyl-C 1-3 -alkyl, phenyl-C 1-3 -alkoxycarbonyl or C 1-6 -alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C 1-3 -alky
  • R a denotes a C 1-8 -alkyl, C 1-7 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl group,
  • R b denotes a hydrogen atom, a C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl group and
  • R c denotes a hydrogen atom or a C 1-3 -alkyl group
  • a group which is negatively charged under physiological conditions is meant a carboxy, hydroxysulphonyl, phosphono, tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C 1-6 -alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C 1-6 -alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C 1-6 -alkylsulphonylaminocarbonyl group.
  • saturated alkyl and alkoxy moieties which contain more than 2 carbon atoms also include the branched isomers thereof such as, for example, the isopropyl, tert.butyl, isobutyl group, etc.
  • X, Y a , Y b and R a to R c are as hereinbefore defined and n denotes the number 3, 4 or 5,
  • n denotes the number 3 or 4,
  • X denotes a carbon-carbon bond or an oxygen atom
  • Y a denotes a carbonyl or sulphonyl group
  • Y b denotes the group —(CH 2 ) m , wherein m denotes the number 2 or 3 and wherein a hydrogen atom may be replaced by a C 1-3 -alkyl group or a methylene group linked to a nitrogen atom may be replaced by a carbonyl group,
  • R a denotes a C 1-4 -alkoxy or phenyl-C 1-3 -alkoxy group
  • a C 1-3 -alkyl group substituted by a C 5-7 -cycloalkyl, phenyl, phenoxy, 1-naphthyl, 2-naphthyl, fluoren-9-yl or heteroaryl group,
  • R 1 denotes a hydrogen, fluorine, chlorine or bromine atom, a cyano, C 1-3 -alkyl, C 3-4 -alkenyl, phenyl, hydroxy, C 1-3 -alkoxy, nitro, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, C 1-3 -alkylcarbonylamino or N-(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino group and
  • R 2 denotes a hydrogen, fluorine, chlorine or bromine atom, a C 1-3 -alkyl, hydroxy or C 1-3 -alkoxy group, wherein in the abovementioned alkyl and alkoxy moieties of the groups R 1 and R 2 the hydrogen atoms may be wholly or partially replaced by fluorine atoms, or
  • R 1 and R 2 together denote a methylenedioxy group
  • R b denotes a C 1-3 -alkoxycarbonyl, C 1-3 -alkoxycarbonyl-C 1-3 -alkylcarbonyl or a R 3 NR 4 —CO group wherein
  • R 3 denotes a hydrogen atom or a C 1-3 -alkyl group
  • R 4 denotes a C 1-6 -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C 3-7 -cycloalkyl, phenyl, naphthyl, pyridyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, phenyl-C 1-3 -alkyl or pyridinyl-C 1-3 -alkyl group,
  • phenyl groups may be substituted in each case by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or by a hydroxy or C 1-3 -alkoxy group,
  • R c denotes a hydrogen atom or a C 1-3 -alkyl group
  • heteroaryl group a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, indolyl or benzimidazolyl group optionally substituted in the carbon skeleton by a C 1-3 -alkyl group, in which a hydrogen atom bound to a nitrogen atom may be replaced by a C 1-3 -alkyl group and wherein the 5-membered monocyclic or benzo-condensed heteroaryl groups containing at least one imino group are bound via a carbon or nitrogen atom,
  • the tricyclic group in the abovementioned general formula I may additionally be substituted by a fluorine or chlorine atom or by a methyl or methoxy group,
  • n denotes the number 4,
  • X denotes a carbon-carbon bond
  • Y a denotes a carbonyl group
  • Y b denotes the group —(CH 2 ) 2 —
  • R a denotes a phenyl-C 1-3 -alkylamino group
  • R 1 denotes a hydrogen, fluorine, chlorine or bromine atom, a cyano or C 1-3 -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and
  • R 2 denotes a hydrogen, fluorine, chlorine or bromine atom
  • R b denotes a R 3 NR 4 —CO group
  • R 3 denotes a hydrogen atom
  • R 4 denotes a C 1-3 -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a phenyl-C 1-3 -alkyl group,
  • phenyl groups may in each case be substituted by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, by a hydroxy or C 1-3 -alkoxy group, and
  • R c denotes a hydrogen atom or a C 1-3 -alkyl group
  • the new compounds are obtained by methods known from the literature, e.g. by the following methods:
  • R b , R c , X, Y b and n are as hereinbefore defined, with a compound of general formula
  • R a and Y a are as hereinbefore defined and
  • Z 1 denotes a hydroxy group, a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or,
  • reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent, expediently at temperatures between ⁇ 50 and 150° C., preferably at temperatures between ⁇ 20 and 80° C.
  • solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane
  • solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane
  • the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 2-dimethylaminopyridine, in the presence of N-ethyl-diisopropylamine (Hunig base), wherein these organic bases may simultaneously serve as solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution expediently at temperatures between ⁇ 50 and 150° C., preferably at temperatures between ⁇ 20 and 80° C.
  • solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydr
  • the reaction is preferably carried out in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N,N′-dicyclohexylcarbodiimide, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine, N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, expedi
  • R b denotes a C 1-6 -alkoxycarbonyl, C 3-7 -cycloalkoxycarbonyl or phenyl-C 1-3 -alkoxycarbonyl group or a R 3 NR 4 —CO group wherein R 3 and R 4 are as hereinbefore defined:
  • R a , R c , X, Y a , Y b and n are as hereinbefore defined, with a compound of general formula
  • R b ′ denotes a C 1-6 -alkoxy, C 3-7 -cycloalkoxy or phenyl-C 1-3 -alkoxy group or a R 3 NR 4 group, wherein R 3 and R 4 are as hereinbefore defined, or with the reactive derivatives thereof.
  • reaction is expediently carried out with a corresponding halide or anhydride of general formula IV in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulpholane optionally in the presence of an inorganic or organic base at temperatures between ⁇ 20 and 200° C., but preferably at temperatures between ⁇ 10 and 160° C. It may, however, also be carried out with the free acid optionally in the presence of an acid-activating agent or a dehydrating agent, e.g.
  • the subsequent acylation is expediently carried out with a corresponding halide, anhydride or isocyanate in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulpholane optionally in the presence of an inorganic or organic base at temperatures between ⁇ 20 and 200° C., but preferably at temperatures between ⁇ 10 and 160° C.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulpholane
  • an inorganic or organic base at temperatures between ⁇ 20 and 200° C., but preferably at temperatures between ⁇ 10 and 160° C.
  • it may also be carried out with the free acid optionally in the presence of an
  • the subsequent reduction of a nitro group is expediently carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as platinum, palladium/charcoal or Raney nickel in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dimethylformamide or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar, with metals such as iron, tin or zinc in the presence of an acid such as acetic acid or hydrochloric acid, with salts such as iron(II)sulphate, tin (II) chloride, sodium sulphide, sodium hydrogen sulphite or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 100° C., but preferably at temperatures between 20 and 60° C.
  • a catalyst such as platinum
  • any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • a protecting group for a hydroxy group may be a trimethylsilyl, tert.butyl-dimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
  • a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
  • protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
  • Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120° C., preferably at temperatures between 10 and 100° C.
  • a silyl group may also be cleaved using tetrabutylammonium fluoride as described hereinbefore.
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100° C., but preferably at temperatures between 20 and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
  • a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • a trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120° C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50° C.
  • an acid such as hydrochloric acid
  • a solvent such as acetic acid at temperatures between 50 and 120° C.
  • sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50° C.
  • the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore.
  • cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
  • the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of geheral formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • the enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • Optically active acids in common use are e.g.
  • An optically active alcohol may be for example (+) or ( ⁇ )-menthol and an optically active acyl group in amides, for example, may be a (+)-or ( ⁇ )-menthyloxycarbonyl.
  • the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained contain an acidic group such as a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
  • Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • a compound of general formula II is obtained for example by reacting a compound of general formula
  • R b , X and n are as hereinbefore defined and
  • Z 2 denotes a nucleofugic leaving group such as a chlorine or bromine atom, with a corresponding piperazine or homopiperazine wherein an imino group may conveniently be protected by a conventional protecting group, e.g. by a tert.butoxycarbonyl or benzyloxycarbonyl group, in a melt or in a solvent such as ethanol, dioxane, tetrahydrofuran, acetonitrile or dimethylformamide, in the presence of a base such as triethylamine or potassium carbonate and at temperatures between 0 and 130° C., but preferably at temperatures between 20 and 80° C. Any protecting group used is subsequently cleaved by methods known from the literature.
  • a conventional protecting group e.g. by a tert.butoxycarbonyl or benzyloxycarbonyl group, in a melt or in a solvent such as ethanol, dioxane, tetrahydrofuran, acet
  • a compound of general formula IV is obtained for example analogously to method a) by reacting a correspondingly substituted carboxylic acid derivative with a compound of general formula III and optionally subsequently cleaving any protecting group used to protect the carboxy group.
  • the compounds of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties.
  • they are valuable inhibitors of the microsomal triglyceride-transfer protein (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoproteins.
  • MTP microsomal triglyceride-transfer protein
  • Inhibitors of MTP were identified by a cell-free MTP activity test. Solubilised liver microsomes from various species (e.g. rat, pig) can be used as the MTP source.
  • Solubilised liver microsomes from various species e.g. rat, pig
  • lipids dissolved in organic solvents were mixed in a suitable ratio and applied as a thin layer to the wall of a glass container by blowing the solvent in a nitrogen current.
  • the solution used to prepare donor vesicles contained 400 ⁇ M of phosphatidyl choline, 75 ⁇ M of cardiolipin and 10 ⁇ M of [ 14 C]-triolein (68,8 ⁇ Ci/mg).
  • a solution of 1.2 mM phosphatidyl choline, 5 ⁇ M triolein and 15 ⁇ M [ 3 H]-dipalmitoylphosphatidyl choline (108 mCi/mg) was used.
  • Vesicles are produced by wetting the dried lipids with test buffer and subsequently ultrasonicating. Vesicle populations of uniform size were obtained by gel filtration of the ultrasonicated lipids.
  • the MTP activity test contains donor vesicles, acceptor vesicles as well as the MTP source in test buffer. Substances were added from concentrated DMSO-containing stock solutions, the final concentration of DMSO in the test was 0.1%.
  • the reaction was started by the addition of MTP. After a corresponding incubation time the transfer process was stopped by the addition of 500 ⁇ l of a SOURCE 30Q anion exchanger suspension (Pharmacia Biotech). The mixture was shaken for 5 minutes and the donor vesicles bound to the anion exchanger material were separated off by centrifuging. The radioactivity of [ 3 H] and [ 14 C] in the supernatant was determined by liquid scintillation measurement and from this the recovery of the acceptor vesicles and the triglyceride transfer speed was calculated.
  • the compounds of general formula I and the physiologically acceptable salts thereof are particularly suitable for lowering the plasma concentration of atherogenic apolipoprotein B (apoB)-containing lipoproteins such as chylomicrons and/or very low density lipoproteins (VLDL) as well as the residues thereof such as low density lipoproteins (LDL) and/or lipoprotein(a) (Lp(a)), for treating hyperlipidaemias, for preventing and treating atherosclerosis and the clinical sequelae thereof, and for preventing and treating related disorders such as diabetes mellitus, adiposity and pancreatitis, oral administration being preferred.
  • apoB apolipoprotein B
  • VLDL very low density lipoproteins
  • LDL low density lipoproteins
  • Lp(a) lipoprotein(a)
  • the daily dose needed to achieve such an effect is between 0.5 and 500 mg, expediently between 1 and 350 mg, but preferably between 5 and 200 mg, in adults.
  • the compounds of formula I prepared according to the invention optionally combined with other active substances such as other lipid-lowering agents, for example HMG-CoA-reductase-inhibitors, cholesterol biosynthesis inhibitors such as squalene synthase inhibitors and squalene cyclase inhibitors, bile acid-binding resins, fibrates, cholesterol resorption inhibitors, niacin, probucol, CETP inhibitors and ACAT inhibitors may be incorporated together with one or more inert conventional carriers and/or diluents, e.g.
  • active substances such as other lipid-lowering agents, for example HMG-CoA-reductase-inhibitors, cholesterol biosynthesis inhibitors such as squalene synthase inhibitors and squalene cyclase inhibitors, bile acid-binding resins, fibrates, cholesterol resorption inhibitors, niacin, probucol, CETP inhibitors and ACAT inhibitors may be incorporated together with one or
  • reaction solution is concentrated by evaporation using the rotary evaporator, the residue is taken up in dichloromethane and extracted with an ammonium hydroxide solution.
  • organic phase is dried over sodium sulphate and the solvent is distilled off.
  • Methyl 9-(4- ⁇ 4-phenyl-acetyl]-piperazin-2-on-1-yl ⁇ -butyl)-9H-fluorene-9-carboxylate is saponified analogously to Example VI and then reacted to form 9-(4- ⁇ 4-phenyl-acetyl]-piperazin-2-on-1-yl ⁇ -butyl)-9H-fluorene-9-carboxylic acid chloride analogously to Example II.
  • composition active substance 5.0 mg lactose monohydrate 70.8 mg microcrystalline cellulose 40.0 mg sodium carboxymethylcellulose, insolubly crosslinked 3.0 mg magnesium stearate 1.2 mg
  • the active substance is mixed for 15 minutes with lactose monohydrate, microcrystalline cellulose and sodium carboxymethylcellulose in a suitable diffusion mixer. Magnesium stearate is added and mixed with the other substances for another 3 minutes.
  • the finished mixture is compressed in a tablet press to form facetted flat round tablets.
  • composition active substance 50.0 mg lactose monohydrate 130.0 mg corn starch 65.0 mg highly dispersed silicon dioxide 2.5 mg magnesium stearate 2.5 mg
  • a starch paste is prepared by swelling some of the corn starch in a suitable amount of hot water. The paste is then left to cool to room temperature.
  • the active substance is premixed for 15 minutes in a suitable mixer with lactose monohydrate and corn starch.
  • the starch paste is added and the mixture is mixed with sufficient water to produce a moist homogeneous mass.
  • the moist mass is passed through a screen with a mesh size of 1.6 mm.
  • the screened granules are dried on racks at about 550C for 12 hours.
  • the finished mixture is packed into empty size 1 hard gelatine capsule shells using a capsule filling machine.
  • composition active substance 200.0 mg lactose-monohydrate 167.0 mg microcrystalline cellulose 80.0 mg hydroxypropyl-methylcellulose, type 2910 10.0 mg poly-1-vinyl-2-pyrrolidone, insolubly crosslinked 20.0 mg magnesium stearate 3.0 mg
  • HPMC is dispersed in hot water. After cooling, the mixture yields a clear solution.
  • the active substance is premixed in a suitable mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose.
  • the HPMC solution is added and the mixing is continued until a homogeneous moist composition is obtained.
  • the moist composition is passed through a screen with a mesh size of 1.6 mm.
  • the screened granules are dried on racks at about 55° C. for 12 hours.
  • the finished mixture is compressed in a tablet press to form oblong tablets (16.2 ⁇ 7.9 mm).

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Cited By (9)

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US20050075367A1 (en) * 2002-02-28 2005-04-07 Atsushi Hagiwara Ester compound and medicinal use thereof
US20050288335A1 (en) * 2001-06-28 2005-12-29 Pfizer Inc Triamide-substituted heterobicyclic compounds
US20060030623A1 (en) * 2004-07-16 2006-02-09 Noboru Furukawa Agent for the treatment or prevention of diabetes, obesity or arteriosclerosis
US20060089392A1 (en) * 2004-10-18 2006-04-27 Atsushi Hagiwara Ester derivatives and medicinal use thereof
US20060153913A1 (en) * 2004-10-25 2006-07-13 Shogo Yamane Solid formulation with improved solubility and stability, and method for producing said formulation
US20060205726A1 (en) * 2003-08-29 2006-09-14 Atsushi Hagiwara Ester derivatives and medical use thereof
US20090030971A1 (en) * 2007-10-20 2009-01-29 Pooja Trivedi System and Method for Transferring Data Among Computing Environments
US20090325980A1 (en) * 2006-10-24 2009-12-31 Lieven Meerpoel Piperidine or piperazine substituted tetrahydro-naphthalene-1-carboxylic acid mtp inhibiting compounds
AU2007310927B2 (en) * 2006-10-24 2012-01-12 Janssen Pharmaceutica Nv MTP inhibiting tetrahydro-naphthalene-1-carboxylic acid derivatives

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DE10200633A1 (de) * 2002-01-10 2003-07-24 Boehringer Ingelheim Pharma Kombination von MTP Inhibitoren oder apoB-Sekretions-Inhibitoren mit Fibraten zur Verwendung als Arzneimittel
EP2225226B1 (de) 2007-12-26 2016-08-17 Critical Outcome Technologies, Inc. Verbindungen und ihre verwending in einem verfahren zur behandlung von krebs
WO2010006438A1 (en) 2008-07-17 2010-01-21 Critical Outcome Technologies Inc. Thiosemicarbazone inhibitor compounds and cancer treatment methods
CA2794952C (en) 2010-04-01 2018-05-15 Critical Outcome Technologies Inc. Compounds and method for treatment of hiv

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US5739135A (en) * 1993-09-03 1998-04-14 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
US5885983A (en) * 1996-05-10 1999-03-23 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
WO1998027979A1 (en) * 1996-12-20 1998-07-02 Bristol-Myers Squibb Company Heterocyclic inhibitors of microsomal triglyceride transfer protein and method

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US20050288335A1 (en) * 2001-06-28 2005-12-29 Pfizer Inc Triamide-substituted heterobicyclic compounds
US7482368B2 (en) 2001-06-28 2009-01-27 Pfizer Inc Triamide-substituted heterobicyclic compounds
US20100158996A1 (en) * 2002-02-28 2010-06-24 Japan Tobacco Inc. Ester compound and medical use thereof
US7625948B2 (en) 2002-02-28 2009-12-01 Japan Tobacco Inc. Ester compound and medicinal use thereof
US20050075367A1 (en) * 2002-02-28 2005-04-07 Atsushi Hagiwara Ester compound and medicinal use thereof
US20060205726A1 (en) * 2003-08-29 2006-09-14 Atsushi Hagiwara Ester derivatives and medical use thereof
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US20060030623A1 (en) * 2004-07-16 2006-02-09 Noboru Furukawa Agent for the treatment or prevention of diabetes, obesity or arteriosclerosis
US20060089392A1 (en) * 2004-10-18 2006-04-27 Atsushi Hagiwara Ester derivatives and medicinal use thereof
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
US20060153913A1 (en) * 2004-10-25 2006-07-13 Shogo Yamane Solid formulation with improved solubility and stability, and method for producing said formulation
AU2007310927B2 (en) * 2006-10-24 2012-01-12 Janssen Pharmaceutica Nv MTP inhibiting tetrahydro-naphthalene-1-carboxylic acid derivatives
US20090325980A1 (en) * 2006-10-24 2009-12-31 Lieven Meerpoel Piperidine or piperazine substituted tetrahydro-naphthalene-1-carboxylic acid mtp inhibiting compounds
US8114880B2 (en) 2006-10-24 2012-02-14 Janssen Pharmaceutica N.V. Piperidine or piperazine substituted tetrahydro-naphthalene-1-carboxylic acid MTP inhibiting compounds
US8158783B2 (en) 2006-10-24 2012-04-17 Janssen Pharmaceutica N.V. MTP inhibiting tetrahydro-naphthalene-1-carboxylic acid derivatives
TWI396688B (zh) * 2006-10-24 2013-05-21 Janssen Pharmaceutica Nv 經六氫吡啶或六氫吡取代的四氫-萘-１-羧酸之ｍｔｐ抑制性化合物
US20090030971A1 (en) * 2007-10-20 2009-01-29 Pooja Trivedi System and Method for Transferring Data Among Computing Environments
US8190707B2 (en) 2007-10-20 2012-05-29 Citrix Systems, Inc. System and method for transferring data among computing environments
US8612546B2 (en) 2007-10-20 2013-12-17 Citrix Systems, Inc. System and method for transferring data among computing environments

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